Extract of Aster glehni ameliorates potassium oxonate-induced hyperuricemia by modulating renal urate transporters and renal inflammation by suppressing TLR4/MyD88 signaling.

Recent studies suggest that Aster glehni extract (AGE) reduces hyperuricemia by preventing xanthine oxidase activity. However, its effect on renal urate transporters responsible for modulating urate excretion has not been examined. This study investigated whether AGE affects gene expressions of urate transporters using potassium oxonate (PO)-induced hyperuricemia rats. Furthermore, the underlying mechanisms of AGE were explored to ameliorate renal inflammation and injury by PO. AGE effectively restored PO-induced dysregulation of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette transporter subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and organic cation transporter 1 (OCT1), resulting in increasing urate excretion. Additionally, AGE suppressed toll-like receptor 4/myeloid differentiation factor 88 (TLR4/MyD88) signaling, phosphorylation of nuclear factor kappa B (NF-κB), and renal production of IFN-γ, IL-1ß, TNF-α, and IL-6. These results suggest that AGE may ameliorate PO-induced hyperuricemia by modulating renal transporters, and further renal inflammation via inhibiting the TLR4/MyD88/NF-κB signaling pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01153-5.

The E2 ubiquitin-conjugating enzyme HIP2 is a crucial regulator of quality control against mutant SOD1 proteotoxicity.

Mutations in superoxide dismutase 1 (SOD1) leading to the formation of intracellular protein aggregates cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of motor neurons. The ALS-linked mutant SOD1 emerged as a possible target for ubiquitin-proteasome system (UPS)-mediated degradation. We aimed to elucidate the role of huntingtin interaction protein 2 (HIP2), an E2 ubiquitin-conjugating enzyme, in the proteotoxicity of mutant SOD1 aggregates. We found that HIP2 interacts with mutant SOD1, but not wild-type SOD1, and is upregulated in response to mutant SOD1 expression. Upregulation of HIP2 protein was observed in the spinal cord of 16-week-old SOD1-G93A transgenic mice. HIP2 further modified mutant SOD1 proteins via K48-linked polyubiquitination and degraded mutant SOD1 proteins through the UPS. Upregulation of HIP2 protected cells from mutant SOD1-induced toxicity. Taken together, our findings demonstrate that HIP2 is a crucial regulator of quality control against the proteotoxicity of mutant SOD1. Our results suggest that modulating HIP2 may represent a novel therapeutic strategy for the treatment of ALS.

Downregulation of APRIN expression increases cancer cell proliferation via an interleukin-6/STAT3/cyclin D axis.

APRIN is a putative tumor suppressor whose expression is low in a variety of cancer cells. While decreased expression of APRIN leads to increased cell proliferation, unfavorable diagnosis or metastases in various cancer types, there is limited knowledge on the cellular mechanism of APRIN in cellular responses. The effect of APRIN depletion on cancer cell proliferation was examined in the present study, and the IL-6/STAT3/cyclin D axis was identified as a novel regulatory mechanism. Stable depletion of APRIN in cancer cells resulted in increased cell proliferation. Cytokine array analysis of the cells revealed that downregulation of APRIN induced secretion of interleukin-6 (IL-6) with corresponding activation of STAT3, a downstream intracellular mediator. Levels of cyclin D1 were increased in cells with APRIN depletion and cyclin D1 expression was associated with increased STAT3 binding on cyclin D1 promoter sequence; assessed by chromatin immunoprecipitation assay. The addition of an IL-6 neutralizing antibody P620 to the cell culture attenuated STAT3 activation and cyclin D1 expression in APRIN-depleted cells with corresponding decrease in cell proliferation. These experiments suggest that APRIN regulates cancer cell proliferation via an IL-6/STAT3/cyclin D axis and that targeting this axis in APRIN-associated cancer might provide a novel therapeutic approach.

ALS-Related Mutant SOD1 Aggregates Interfere with Mitophagy by Sequestering the Autophagy Receptor Optineurin.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive demise of motor neurons. One of the causes of familial ALS is the mutation of the gene encoding superoxide dismutase 1 (SOD1), which leads to abnormal protein aggregates. How SOD1 aggregation drives ALS is still poorly understood. Recently, ALS pathogenesis has been functionally implicated in mitophagy, specifically the clearance of damaged mitochondria. Here, to understand this mechanism, we investigated the relationship between the mitophagy receptor optineurin and SOD1 aggregates. We found that mutant SOD1 (mSOD1) proteins associate with and then sequester optineurin, which is required to form the mitophagosomes, to aggregates in N2a cells. Optineurin recruitment into mSOD1 aggregates resulted in a reduced mitophagy flux. Furthermore, we observed that an exogenous augmentation of optineurin alleviated the cellular cytotoxicity induced by mSOD1. Taken together, these studies demonstrate that ALS-linked mutations in SOD1 interfere with the mitophagy process through optineurin sequestration, suggesting that the accumulation of damaged mitochondria may play a crucial role in the pathophysiological mechanisms contributing to ALS.

Fermented Platycodon grandiflorum Extracts Relieve Airway Inflammation and Cough Reflex Sensitivity In Vivo.

Platycodon grandiflorum (PG) has been extensively utilized as an herb to relieve phlegm. In this study, the effects of PG root extracts on airway inflammation and cough reflex were investigated, especially using fermented PG extracts (FPE) to increase an active compound, platycodin D by fermentation. FPE significantly reduced the numbers of eosinophils and total cells in the bronchoalveolar lavage fluid (BALF) obtained from lipopolysaccharide/ovalbumin (LPS/OVA)-induced asthma mice versus those of vehicle control. Moreover, in the BALF and the serum, FPE significantly reduced the concentration of IL-17E, a proinflammatory cytokine that causes TH2 immunity, including eosinophil amplification. It was also demonstrated that FPE might relieve inflammations through histological analysis of the lung separated from each mouse. Furthermore, in cough reflex guinea pigs induced by citric acid treatment, FPE treatment significantly reduced the number of coughs versus that of vehicle control, and consequently decreased cough reflex sensitivity. In addition, the total cell number and eosinophils significantly decreased in the BALF obtained from each guinea pig versus that of vehicle control. In in vitro study, pretreatment with FPE in LPS-stimulated RAW264.7 cells significantly reduced the levels of proinflammatory cytokines such as TNF-α, IL-6, and IL-1ß, and inducible nitric oxide synthases (iNOS). Therefore, we demonstrated that FPE relieved airway inflammation and cough reflex sensitivity in vivo, and exhibited anti-inflammatory effects through suppression of iNOS and several proinflammatory cytokines. These findings suggest that FPE might have a beneficial effect on respiratory health, and may be useful as a functional food to prevent respiratory diseases.

Effects of Aster glehni Extract on Serum Uric Acid in Subjects with Mild Hyperuricemia: A Randomized, Placebo-Controlled Trial.

Aster glehni extracts (AGE) reduced serum uric acid levels in hyperuricemia rats in several previous studies. However, its efficacy in human has not been yet explored. This study aimed at investigating the efficacy and safety of AGE on the anti-hyperuricemia effect in subjects with slightly high serum uric acid. A randomized, double-blinded, placebo-controlled clinical trial was conducted for 12 weeks. Eligible subjects were randomly assigned to either AGE (480 mg/day) or placebo. The primary endpoint was the change in serum uric acid concentrations from baseline to follow-up time points. The secondary endpoints were the change of serum xanthine oxidase activity, and the levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) in the blood from baseline to follow-up time points. Safety was assessed by clinical laboratory parameters and adverse events reported by subjects. Six weeks of AGE supplementation significantly reduced serum uric acid level from baseline (P = .0468) but at the end of the intervention the participants did not show the beneficial effect of AGE supplementation. Also, the serum uric acid level in the AGE group was not significantly different at the follow-up time points, when compared with placebo. The mean changes of secondary endpoints from baseline to each time point did not show significant differences within and between the two groups. There were no adverse events reported by subjects or changes in safety parameters after intervention. In conclusion, AGE supplementation for 12 weeks did not show significant benefits for reducing serum uric acid concentrations in subjects with mild hyperuricemia.

Dopamine receptor D2 activation suppresses the radiosensitizing effect of aripiprazole via activation of AMPK.

Drug repositioning has garnered attention as an alternative strategy to the discovery and development of novel anticancer drug candidates. In this study, we screened 321 FDA-approved drugs against nonirradiated and irradiated MCF-7 cells, revealing that aripiprazole, a dopamine receptor D2 (D2R) partial agonist, enhances the radiosensitivity of MCF-7 cells. Unexpectedly, D2R-selective antagonist treatment significantly enhanced the radiosensitizing effects of aripiprazole and prevented aripiprazole-induced 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Direct AMPK activation with A769662 treatment blunted the radiosensitizing effects of aripiprazole. These results indicate that aripiprazole has potential as a radiosensitizing drug. Furthermore, prevention of D2R/AMPK activation might enhance these anticancer effects of aripiprazole in breast cancer cells.

Hip2 ubiquitin-conjugating enzyme has a role in UV-induced G1/S arrest and re-entry.

Regulation of cell cycle arrest and re-entry triggered by DNA damage is vital for cell division and growth and is also involved in cell survival. UV radiation can generate lesions in the DNA, which results in cell cycle arrest and the induction of the DNA repair process. However, the mechanism of promoting cell cycle progression following DNA repair is elusive. The primary aim of this study is to investigate whether Hip2 ubiquitin-conjugating enzyme has a role in UV-induced G1/S arrest and re-entry. The phase of HEK293 cells was synchronized at the G1/S border using thymidine. The synchronously proliferating cells were exposed to UV radiation to cause DNA damage. We investigated the expression of p53, Hip2, p21, cyclin D and E proteins that are involved in the cell cycle progression. Finally, we examined changes in the phosphorylation of Hip2 after UV radiation treatment using the pIMAGO™ assay. When cells were exposed to UV radiation, expression of p53 was elevated, and the cell cycle was arrested at the G1/S boundary. In response to the increased p53 level, Hip2 became phosphorylated and activated through the inhibition of its degradation. The phosphorylated Hip2 inhibited p53, thereby suppressing the expression of p21, a downstream signal, and sequentially stimulating cyclin D and cyclin E to induce re-entry to the cell cycle. Our studies demonstrate that Hip2 works as a regulator in UV-induced cell cycle arrest and re-entry.

The C-terminal region of ATG101 bridges ULK1 and PtdIns3K complex in autophagy initiation.

The initiation of macroautophagy/autophagy is tightly regulated by the upstream ULK1 kinase complex, which affects many downstream factors including the PtdIns3K complex. The phosphorylation of the right position at the right time on downstream molecules is governed by proper complex formation. One component of the ULK1 complex, ATG101, known as an accessory protein, is a stabilizer of ATG13 in cells. The WF finger region of ATG101 plays an important role in the recruitment of WIPI1 (WD repeat domain, phosphoinositide interacting protein 1) and ZFYVE1 (zinc finger FYVE-type containing 1). Here, we report that the C-terminal region identified in the structure of the human ATG101-ATG13HORMA complex is responsible for the binding of the PtdIns3K complex. This region adopts a ß-strand conformation in free ATG101, but either an α-helix or random coil in our ATG101-ATG13HORMA complex, which protrudes from the core and interacts with other molecules. The C-terminal deletion of ATG101 shows a significant defect in the interaction with PtdIns3K components and subsequently impairs autophagosome formation. This result clearly presents an additional role of ATG101 for bridging the ULK1 and PtdIns3K complexes in the mammalian autophagy process. Abbreviations: ATG: autophagy related; BECN1: beclin 1; GFP: green fluorescent protein; HORMA: Hop1p/Rev7p/MAD2; HsATG13HORMA: HORMA domain of ATG13 from Homo sapiens; KO: knockout; MAD2: mitotic arrest deficient 2 like 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAXS: small-angle X-ray scattering; ScAtg13HORMA: HORMA domain of Atg13 from Sccharomyces cerevisiae; SEC-SAXS: size-exclusion chromatography with small-angle X-ray scattering; SpAtg13HORMA: HORMA domain of Atg13 from Schizosaccharomyces pombe; SQSTM1/p62: sequestosome 1; ULK1: unc51-like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain: phosphoinositide interacting 1; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.

Cold atmospheric plasma (CAP), a novel physicochemical source, induces neural differentiation through cross-talk between the specific RONS cascade and Trk/Ras/ERK signaling pathway.

Plasma, formed by ionization of gas molecules or atoms, is the most abundant form of matter and consists of highly reactive physicochemical species. In the physics and chemistry fields, plasma has been extensively studied; however, the exact action mechanisms of plasma on biological systems, including cells and humans, are not well known. Recent evidence suggests that cold atmospheric plasma (CAP), which refers to plasma used in the biomedical field, may regulate diverse cellular processes, including neural differentiation. However, the mechanism by which these physicochemical signals, elicited by reactive oxygen and nitrogen species (RONS), are transmitted to biological system remains elusive. In this study, we elucidated the physicochemical and biological (PCB) connection between the CAP cascade and Trk/Ras/ERK signaling pathway, which resulted in neural differentiation. Excited atomic oxygen in the plasma phase led to the formation of RONS in the PCB network, which then interacted with reactive atoms in the extracellular liquid phase to form nitric oxide (NO). Production of large amounts of superoxide radical (O2-) in the mitochondria of cells exposed to CAP demonstrated that extracellular NO induced the reversible inhibition of mitochondrial complex IV. We also demonstrated that cytosolic hydrogen peroxide, formed by O2- dismutation, act as an intracellular messenger to specifically activate the Trk/Ras/ERK signaling pathway. This study is the first to elucidate the mechanism linking physicochemical signals from the CAP cascade to the intracellular neural differentiation signaling pathway, providing physical, chemical and biological insights into the development of therapeutic techniques to treat neurological diseases.

NABi, a novel ß-sheet breaker, inhibits Aß aggregation and neuronal toxicity: Therapeutic implications for Alzheimer's disease.

Amyloid beta (Aß) aggregates are an important therapeutic target for Alzheimer's disease (AD), a fatal neurodegenerative disease. To date, AD still remains a big challenge due to no effective treatments. Based on the property that Aß aggregates have the cross-ß-structure, a common structural feature in amyloids, we systemically designed the Aß-aggregation inhibitor that maintains Aß-interacting ability but removes toxic part from SOD1 (superoxide dismutase 1)-G93A. We identified NABi (Natural Aß Binder and Aß-aggregation inhibitor) composed of ß2-3 strands, a novel breaker of Aß aggregation, which does not self-aggregate and has no cytotoxicity at all. The NABi blocks Aß-fibril formation in vitro and in vivo and prevents neuronal cell death, a hallmark of AD pathogenesis. Such anti-amyloidogenic properties can provide novel strategies for treating AD. Furthermore, our study provides molecular insights into the design of amyloidogenic inhibitors to cure various neurodegenerative and amyloid-associated diseases, as NABi would regulate aggregation of other toxic ß-sheet proteins other than Aß.

Ataxin-1 is involved in tumorigenesis of cervical cancer cells via the EGFR-RAS-MAPK signaling pathway.

Ataxin-1 (ATXN1) is a coregulator protein within which expansion of the polyglutamine tract causes spinocerebellar ataxia type 1, an autosomal dominant neurodegenerative disorder. Previously, we reported that ATXN1 regulates the epithelial-mesenchymal transition of cervical cancer cells. In the present study, we demonstrate that ATXN1 is involved in cervical cancer tumorigenesis by promoting the proliferation of human cervical cancer cells. Chromatin immunoprecipitation assays showed that ATXN1 bound to the promoter region within cyclin D1 and activated cyclin D1 transcription, resulting in cell proliferation. ATXN1 promoted cyclin D1 expression through the EGFR-RAS-MAPK signaling pathway. Mouse xenograft tumorigenicity assays showed that ATXN1 downregulation inhibited tumorigenesis in cervical cancer cell lines in nude mice. Human cervical cancer tissue microarrays and immunohistochemical techniques showed that ATXN1 was significantly upregulated in many such tissues. Our results suggest that ATXN1 plays an important role in cervical cancer tumorigenesis and is a prognostic marker for cervical cancer.

ALS-linked mutant SOD1 proteins promote Aß aggregates in ALS through direct interaction with Aß.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons. Aggregation of ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) is a hallmark of a subset of familial ALS (fALS). Recently, intracellular amyloid-ß (Aß) is detected in motor neurons of both sporadic and familial ALS. We have previously shown that intracellular Aß specifically interacts with G93A, an ALS-linked SOD1 mutant. However, little is known about the pathological and biological effect of this interaction in neurons. In this study, we have demonstrated that the Aß-binding region is exposed on the SOD1 surface through the conformational changes due to misfolding of SOD1. Interestingly, we found that the intracellular aggregation of Aß is enhanced through the direct interaction of Aß with the Aß-binding region exposed to misfolded SOD1. Ultimately, increased Aß aggregation by this interaction promotes neuronal cell death. Consistent with this result, Aß aggregates was three-fold higher in the brains of G93A transgenic mice than those of non Tg. Our study provides the first direct evidence that Aß, an AD-linked factor, is associated to the pathogenesis of ALS and provides molecular clues to understand common aggregation mechanisms in the pathogenesis of neurodegenerative diseases. Furthermore, it will provide new insights into the development of therapeutic approaches for ALS.

CIB1 protects against MPTP-induced neurotoxicity through inhibiting ASK1.

Calcium and integrin binding protein 1 (CIB1) is a calcium-binding protein that was initially identified as a binding partner of platelet integrin αIIb. Although CIB1 has been shown to interact with multiple proteins, its biological function in the brain remains unclear. Here, we show that CIB1 negatively regulates degeneration of dopaminergic neurons in a mouse model of Parkinson's disease using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Genetic deficiency of the CIB1 gene enhances MPTP-induced neurotoxicity in dopaminergic neurons in CIB1-/- mice. Furthermore, RNAi-mediated depletion of CIB1 in primary dopaminergic neurons potentiated 1-methyl-4-phenyl pyrinidium (MPP+)-induced neuronal death. CIB1 physically associated with apoptosis signal-regulating kinase 1 (ASK1) and thereby inhibited the MPP+-induced stimulation of the ASK1-mediated signaling cascade. These findings suggest that CIB1 plays a protective role in MPTP/MPP+-induced neurotoxicity by blocking ASK1-mediated signaling.

Harmless effects of argon plasma on caudal fin regeneration and embryogenesis of zebrafish: novel biological approaches for safe medical applications of bioplasma.

The argon plasma jet (Ar-PJ) is widely used in medical fields such as dermatology and dentistry, and it is considered a promising tool for cancer therapy. However, the in vivo effects of Ar-PJ for medical uses have not yet been investigated, and there are no biological tools to determine the appropriate clinical dosages of Ar-PJ. In this study, we used the caudal fin and embryo of zebrafish as novel in vivo tools to evaluate the biosafety of Ar-PJ. Typically, Ar-PJ is known to induce cell death in two-dimensional (2D) cell culture systems. By contrast, no detrimental effects of Ar-PJ were shown in our 3D zebrafish systems composed of 2D cells. The Ar-PJ-treated caudal fins grew by an average length of 0.7 mm, similar to the length of the normally regenerating fins. Remarkably, Ar-PJ did not affect the expression patterns of Wnt8a and ß-Catenin, which play important roles in fin regeneration. In the embryo system, 85% of the Ar-PJ-treated embryos hatched, and the lateral length of these embryos was ~3.3 mm, which are equivalent to the lengths of normal embryos. In particular, vasculogenesis, which is the main cellular process during tissue regeneration and embryogenesis, occurred normally under the Ar-PJ dose used in this study. Therefore, our biosafety evaluation tools that use living model systems can be used to provide an experimental guideline to determine the clinically safe dosage of Ar-PJ.

Amyotrophic lateral sclerosis-related mutant superoxide dismutase 1 aggregates inhibit 14-3-3-mediated cell survival by sequestration into the JUNQ compartment.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss in the spinal cord and brain. Mutations in the superoxide dismutase 1 (SOD1) gene have been linked to familial ALS. To elucidate the role of SOD1 mutations in ALS, we investigated 14-3-3, a crucial regulator of cell death that was identified in patients with familial ALS. In a transgenic mouse model (SOD1-G93A) of ALS, 14-3-3 co-localized with mutant SOD1 aggregates and was more insoluble in the spinal cords of mutant SOD1 transgenic mice than in those of wild-type mice. Immunofluorescence and co-immunoprecipitation experiments showed that the 14-3-3ɛ and θ isoforms interact with mutant SOD1 aggregates in the juxtanuclear quality control compartment of N2a neuroblastoma cells. Fluorescence loss in photobleaching experiments revealed that movement of the isoforms of 14-3-3 was markedly reduced in SOD1 aggregates. Bax translocation into and cytochrome c release from the mitochondria were promoted by the sequestration of 14-3-3 into mutant SOD1 aggregates, increasing cell death. Mutant SOD1 aggregates were dissolved by the Hsp104 chaperone, which increased the interaction of 14-3-3 with Bax, reducing cell death. Our study demonstrates that mutant SOD1 inhibits 14-3-3-mediated cell survival. This information may contribute to the identification of a novel therapeutic target for ALS.

Selenoprotein S is required for clearance of C99 through endoplasmic reticulum-associated degradation.

Amyloid beta precursor protein (APP) is normally cleaved by α-secretase, but can also be cleaved by ß-secretase (BACE1) to produce C99 fragments in the endoplasmic reticulum (ER) membrane. C99 is subsequently cleaved to amyloid ß (Aß), the aggregation of which is known to cause Alzheimer's disease. Therefore, C99 removing is for preventing the disease. Selenoprotein S (SelS) is an ER membrane protein participating in endoplasmic reticulum-associated degradation (ERAD), one of the stages in resolving ER stress of misfolded proteins accumulated in the ER. ERAD has been postulated as one of the processes to degrade C99; however, it remains unclear if the degradation depends on SelS. In this study, we investigated the effect of SelS on C99 degradation. We observed that both SelS and C99 were colocalized in the membrane fraction of mouse neuroblastoma Neuro2a (N2a) cells. While the level of SelS was increased by ER stress, the level of C99 was decreased. However, despite the induction of ER stress, there was no change in the amount of C99 in SelS knock-down cells. The interaction of C99 with p97(VCP), an essential component of the ERAD complex, did not occur in SelS knock-down cells. The ubiquitination of C99 was decreased in SelS knock-down cells. We also found that the extracellular amount of Aß1-42 was relatively higher in SelS knock-down cells than in control cells. These results suggest that SelS is required for C99 degradation through ERAD, resulting in inhibition of Aß production.

Ataxin-1 regulates epithelial-mesenchymal transition of cervical cancer cells.

The mutant form of the protein ataxin-1 (ATXN1) causes the neurodegenerative disease spinocerebellar ataxia type-1. Recently, ATXN1 was reported to enhance E-cadherin expression in the breast cancer cell line MCF-7, suggesting a potential association between ATXN1 and cancer development. In the present study, we discovered a novel mechanism through which ATXN1 regulates the epithelial-mesenchymal transition (EMT) of cancer cells. Hypoxia-induced upregulation of the Notch intracellular domain expression decreased ATXN1 expression via MDM2-associated ubiquitination and degradation. In cervical cancer cells, ATXN1 knockdown induced EMT by directly regulating Snail expression, leading to matrix metalloproteinase activation and the promotion of cell migration and invasion. These findings provide insights into a novel mechanism of tumorigenesis and will facilitate the development of new and more effective therapies for cancer.

The New Approach for Establishing the Cellular Response Guideline for Medical Applications of Polydiacetylene as Innovative Parameters.

Argon plasma jet (Ar-PJ) has been widely used in clinical medicine; however, the cellular effects of Ar-PJ therapy applying to living tissues have not been clarified yet. It is necessary to investigate cellular responses to Ar-PJ in establishing guidelines on the therapeutic use of Ar-PJ. Interestingly, in the Ar-PJ-treated cells, the fragmented mitochondria, a typical cellular stress indicator, were discovered even in the cells located in the live zones (1∼3 zones). Using microscopic measurements of the mitochondrial length, we found that the fragmented mitochondria were mainly in the zones 1 and 2, the closest to the direct exposure point of Ar-PJ. Whereas, the mitochondria in the zone 4 retained their lengths to normal. This quantitative measurement of mitochondrial morphology was combined with the color scores of the polymerizable supramolecular (PS) sensor in diagnostic categories. The results demonstrate that the mitochondrial length (0.98∼3.94 µm) is inversely proportional to the PS sensor color scores (87∼0) in the zones 1∼4. On the combination of these three diagnostic parameters, the effective range of Ar-PJ for cellular responses was determined: the zones 1∼3, the color scores 87∼12 and the mitochondrial lengths 0.98∼2.57 µm. Our study is the first demonstration of mitochondrial fragmentation in response to Ar-PJ and the first attempt to establish the diagnostic guideline for Ar-PJ therapies by combinations with biological, physical and chemical aspects. Thus, this study will make great advances in the field of bioplasma applications.

Pathogenic Role of Serine Protease HtrA2/Omi in Neurodegenerative Diseases.

High-temperature-requirement A2 (HtrA2)/Omi/PARK13 is a serine protease with extensive homology to the Escherichia coli HtrAs that are required for bacterial survival at high temperatures. The HtrA2 protein is a key modulator of mitochondrial molecular quality control but under stressful conditions it is released into the cytosol, where it promotes cell death by various pathways, including caspase-dependent pathway and ER stress-mediated apoptosis. Recently, the HtrA2 protein has received great attention for its potential role in neurodegeneration. Here, we review the current knowledge and pathophysiological functions of the HtrA2 protein in neurodegenerative disorders such as Parkinson's and Alzheimer's disease.